Cannabis (marijuana, MJ) is the most widely used illicit drug. At the same time, there is growing medical use of MJ and other cannabinoids for treatment of pain and a range of disorders. As availability and use increase, there is concern regarding the consequences of MJ use, particularly for women who appear to be more sensitive to many effects of MJ. Unfortunately, women MJ users are an understudied population. Women show accelerated trajectories from first MJ use to the development of cannabis use disorder (CUD), experience more severe withdrawal, and worse treatment outcomes for CUD treatment, when compared to men. The rewarding and dependence producing effects of MJ are primarily due to ?-9-tetrahydrocannabinol (THC), the main psychoactive component of MJ, and its actions on cannabinoid type 1 receptors (CB1R). CB1R are widely distributed in the human brain and modulate multiple biological processes including regulation of mood, stress, pain, motor function, learning and memory. The proposed studies examine the role of brain CB1R on severity of MJ withdrawal, craving and negative mood during abstinence in women under experimentally rigorous conditions. Women, who are daily MJ users and meet DSM-5 criteria for moderate to severe CUD will be studied under an inpatient protocol that includes controlled smoked MJ administration, monitored MJ abstinence and 11C-OMAR PET imaging of CB1R during peak withdrawal. CB1R availability will be determined for key brain regions associated with drug reward (nucleus accumbens), mood regulation (amygdala and hippocampus), motor function and habit learning (caudate, putamen, globus pallidus) and cognition (frontal cortex). PET scans will also be completed in matched controls (no MJ use). Aim 1 will examine CB1R availability (VT ) in female MJ users and matched controls. We hypothesis that, when compared to controls, female MJ users will have lower VT , and the magnitude of downregulation will be correlated with severity of CUD. Aim 2 will evaluate whether severity of withdrawal during MJ abstinence is negatively associated with CB1R VT in female MJ users. We hypothesis that severity of withdrawal symptoms, negative mood and craving will be correlated with lower VT, particularly in the amygdala and hippocampus. Our exploratory aims will examine cognitive performance and subjective effects before and after smoked MJ administration in MJ users and explore the relationship of these measures to CB1 availability. The results of this study will provide needed preliminary data on whether CB1R may contribute to increased severity of MJ withdrawal in women, and will provide new information towards our understanding of cannabinoid mechanisms in MJ sensitivity and CUD in women. Given that the primary pharmacological treatments for CUD are those that act via the CB1R, and that women account for half of CUD treatment seekers, increasing our understanding of MJ effects on the brain and behavior in women is critical. The public health importance of this study includes identification of sex-specific symptoms, and the mechanisms that modulate them for improved treatment approaches.